3wzd: Difference between revisions

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==KDR in complex with ligand lenvatinib==
==KDR in complex with ligand lenvatinib==
<StructureSection load='3wzd' size='340' side='right' caption='[[3wzd]], [[Resolution|resolution]] 1.57&Aring;' scene=''>
<StructureSection load='3wzd' size='340' side='right'caption='[[3wzd]], [[Resolution|resolution]] 1.57&Aring;' scene=''>
== Structural highlights ==
== Structural highlights ==
<table><tr><td colspan='2'>[[3wzd]] is a 1 chain structure with sequence from [http://en.wikipedia.org/wiki/Human Human]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=3WZD OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=3WZD FirstGlance]. <br>
<table><tr><td colspan='2'>[[3wzd]] is a 1 chain structure with sequence from [https://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=3WZD OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=3WZD FirstGlance]. <br>
</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=DTT:2,3-DIHYDROXY-1,4-DITHIOBUTANE'>DTT</scene>, <scene name='pdbligand=EDO:1,2-ETHANEDIOL'>EDO</scene>, <scene name='pdbligand=GOL:GLYCEROL'>GOL</scene>, <scene name='pdbligand=LEV:4-{3-CHLORO-4-[(CYCLOPROPYLCARBAMOYL)AMINO]PHENOXY}-7-METHOXYQUINOLINE-6-CARBOXAMIDE'>LEV</scene>, <scene name='pdbligand=SO4:SULFATE+ION'>SO4</scene></td></tr>
</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 1.57&#8491;</td></tr>
<tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[3wze|3wze]]</td></tr>
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=DTT:2,3-DIHYDROXY-1,4-DITHIOBUTANE'>DTT</scene>, <scene name='pdbligand=EDO:1,2-ETHANEDIOL'>EDO</scene>, <scene name='pdbligand=GOL:GLYCEROL'>GOL</scene>, <scene name='pdbligand=LEV:4-{3-CHLORO-4-[(CYCLOPROPYLCARBAMOYL)AMINO]PHENOXY}-7-METHOXYQUINOLINE-6-CARBOXAMIDE'>LEV</scene>, <scene name='pdbligand=SO4:SULFATE+ION'>SO4</scene></td></tr>
<tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">KDR, FLK1, VEGFR2 ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 HUMAN])</td></tr>
<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=3wzd FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=3wzd OCA], [https://pdbe.org/3wzd PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=3wzd RCSB], [https://www.ebi.ac.uk/pdbsum/3wzd PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=3wzd ProSAT]</span></td></tr>
<tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[http://en.wikipedia.org/wiki/Receptor_protein-tyrosine_kinase Receptor protein-tyrosine kinase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=2.7.10.1 2.7.10.1] </span></td></tr>
<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=3wzd FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=3wzd OCA], [http://pdbe.org/3wzd PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=3wzd RCSB], [http://www.ebi.ac.uk/pdbsum/3wzd PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=3wzd ProSAT]</span></td></tr>
</table>
</table>
== Disease ==
[[http://www.uniprot.org/uniprot/VGFR2_HUMAN VGFR2_HUMAN]] Defects in KDR are associated with susceptibility to hemangioma capillary infantile (HCI) [MIM:[http://omim.org/entry/602089 602089]]. HCI are benign, highly proliferative lesions involving aberrant localized growth of capillary endothelium. They are the most common tumor of infancy, occurring in up to 10% of all births. Hemangiomas tend to appear shortly after birth and show rapid neonatal growth for up to 12 months characterized by endothelial hypercellularity and increased numbers of mast cells. This phase is followed by slow involution at a rate of about 10% per year and replacement by fibrofatty stroma.<ref>PMID:11807987</ref> <ref>PMID:18931684</ref>  Note=Plays a major role in tumor angiogenesis. In case of HIV-1 infection, the interaction with extracellular viral Tat protein seems to enhance angiogenesis in Kaposi's sarcoma lesions.
== Function ==
[[http://www.uniprot.org/uniprot/VGFR2_HUMAN VGFR2_HUMAN]] Tyrosine-protein kinase that acts as a cell-surface receptor for VEGFA, VEGFC and VEGFD. Plays an essential role in the regulation of angiogenesis, vascular development, vascular permeability, and embryonic hematopoiesis. Promotes proliferation, survival, migration and differentiation of endothelial cells. Promotes reorganization of the actin cytoskeleton. Isoforms lacking a transmembrane domain, such as isoform 2 and isoform 3, may function as decoy receptors for VEGFA, VEGFC and/or VEGFD. Isoform 2 plays an important role as negative regulator of VEGFA- and VEGFC-mediated lymphangiogenesis by limiting the amount of free VEGFA and/or VEGFC and preventing their binding to FLT4. Modulates FLT1 and FLT4 signaling by forming heterodimers. Binding of vascular growth factors to isoform 1 leads to the activation of several signaling cascades. Activation of PLCG1 leads to the production of the cellular signaling molecules diacylglycerol and inositol 1,4,5-trisphosphate and the activation of protein kinase C. Mediates activation of MAPK1/ERK2, MAPK3/ERK1 and the MAP kinase signaling pathway, as well as of the AKT1 signaling pathway. Mediates phosphorylation of PIK3R1, the regulatory subunit of phosphatidylinositol 3-kinase, reorganization of the actin cytoskeleton and activation of PTK2/FAK1. Required for VEGFA-mediated induction of NOS2 and NOS3, leading to the production of the signaling molecule nitric oxide (NO) by endothelial cells. Phosphorylates PLCG1. Promotes phosphorylation of FYN, NCK1, NOS3, PIK3R1, PTK2/FAK1 and SRC.<ref>PMID:19668192</ref> <ref>PMID:1417831</ref> <ref>PMID:7929439</ref> <ref>PMID:9160888</ref> <ref>PMID:9837777</ref> <ref>PMID:9804796</ref> <ref>PMID:10600473</ref> <ref>PMID:10102632</ref> <ref>PMID:11387210</ref> <ref>PMID:12649282</ref> <ref>PMID:15026417</ref> <ref>PMID:15215251</ref> <ref>PMID:15962004</ref> <ref>PMID:16966330</ref> <ref>PMID:17303569</ref> <ref>PMID:19834490</ref> <ref>PMID:20179233</ref> <ref>PMID:20224550</ref> <ref>PMID:20705758</ref> <ref>PMID:10368301</ref> <ref>PMID:18529047</ref> <ref>PMID:20080685</ref> 
<div style="background-color:#fffaf0;">
<div style="background-color:#fffaf0;">
== Publication Abstract from PubMed ==
== Publication Abstract from PubMed ==
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==See Also==
==See Also==
*[[Vascular Endothelial Growth Factor Receptor|Vascular Endothelial Growth Factor Receptor]]
*[[3D structures of vascular endothelial growth factor receptor|3D structures of vascular endothelial growth factor receptor]]
== References ==
== References ==
<references/>
<references/>
__TOC__
__TOC__
</StructureSection>
</StructureSection>
[[Category: Human]]
[[Category: Homo sapiens]]
[[Category: Receptor protein-tyrosine kinase]]
[[Category: Large Structures]]
[[Category: Ikemori_Kawada, M]]
[[Category: Ikemori_Kawada M]]
[[Category: Inoue, A]]
[[Category: Inoue A]]
[[Category: Matsui, J]]
[[Category: Matsui J]]
[[Category: Okamoto, K]]
[[Category: Okamoto K]]
[[Category: Kdr receptor kinase]]
[[Category: Transferase-transferase inhibitor complex]]

Latest revision as of 05:37, 21 November 2024

KDR in complex with ligand lenvatinibKDR in complex with ligand lenvatinib

Structural highlights

3wzd is a 1 chain structure with sequence from Homo sapiens. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Method:X-ray diffraction, Resolution 1.57Å
Ligands:, , , ,
Resources:FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Publication Abstract from PubMed

Lenvatinib is an oral multikinase inhibitor that selectively inhibits vascular endothelial growth factor (VEGF) receptors 1 to 3 and other proangiogenic and oncogenic pathway-related receptor tyrosine kinases. To elucidate the origin of the potency of lenvatinib in VEGF receptor 2 (VEGFR2) inhibition, we conducted a kinetic interaction analysis of lenvatinib with VEGFR2 and X-ray analysis of the crystal structure of VEGFR2-lenvatinib complexes. Kinetic analysis revealed that lenvatinib had a rapid association rate constant and a relatively slow dissociation rate constant in complex with VEGFR2. Co-crystal structure analysis demonstrated that lenvatinib binds at its ATP mimetic quinoline moiety to the ATP binding site and to the neighboring region via a cyclopropane ring, adopting an Asp-Phe-Gly (DFG)-"in" conformation. These results suggest that lenvatinib is very distinct in its binding mode of interaction compared to the several approved VEGFR2 kinase inhibitors.

Distinct binding mode of multikinase inhibitor lenvatinib revealed by biochemical characterization.,Okamoto K, Ikemori-Kawada M, Jestel A, von Konig K, Funahashi Y, Matsushima T, Tsuruoka A, Inoue A, Matsui J ACS Med Chem Lett. 2014 Nov 17;6(1):89-94. doi: 10.1021/ml500394m. eCollection, 2015 Jan 8. PMID:25589937[1]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

See Also

References

  1. ↑ Okamoto K, Ikemori-Kawada M, Jestel A, von Konig K, Funahashi Y, Matsushima T, Tsuruoka A, Inoue A, Matsui J. Distinct binding mode of multikinase inhibitor lenvatinib revealed by biochemical characterization. ACS Med Chem Lett. 2014 Nov 17;6(1):89-94. doi: 10.1021/ml500394m. eCollection, 2015 Jan 8. PMID:25589937 doi:http://dx.doi.org/10.1021/ml500394m

3wzd, resolution 1.57Å

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